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20th October 2014 @ 08:50

Summary:

Cross-coupling of the product from TF2-1 and the leftover product from PT-1-20-2 .The procedure used was analogous to that of TF3-1 and PT-22.

Hazard and Risk Assessment:

RA TF4-1.doc

Reaction Scheme:

Procedure:

The procedure was analogous to the syntheses of TF3-1 and PT-22, using the methylated boronic acid pinocol ester instead (which was fortunately in stock).

6-bromo-7-methylthieno[3,2-d]pyrimidin-4-amine [TF2] (17.05 mg, 0.070 mmol, 1 eq), methylated MNR-103 (28.3 mg, 0.078 mmol, 1.2 eq) and Pd(dppf)Cl2 (9.64 mg, 20mol%) were dissolved in isopropyl alcohol (1.2 mL). Potassium carbonate solution (1M, 0.36 mL) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel.

The product was then purified using column chromatography (0-10% methanol in chloroform for 20 tubes) and evaporated to dryness to give a yield of 20.0mg (0.060 mmol, 85.7%) of pale brown product. The solid was soluble in methanol, moreso than the previous product (TF3-1).

Data:

TF4-1 1H MeOD Crude.pdf
TF4-1 1H MeOD.pdf
TF4-1 13C MeOD.pdf
TF4-1 COSY MeOD.pdf
TF4-1 HMBC MeOD.pdf
TF4-1 HSQC MeOD.pdf
TF4-1 DEPT-135 MeOD.pdf
TF4-1 NOESY MeOD.pdf
TF4-1 Raw.tar
TF4-1 Accurate Mass Spec.jpg
TF4-1 Nominal Mass Spec Zoomed.jpg
TF4-1 Nominal Mass Spec.jpg
TF4-1.png
TF4-1 Synthesis.png

InChi:

InChI=1S/C14H14N4O2S2/c1-7-3-4-9(22(16,19)20)5-10(7)12-8(2)11-13(21-12)14(15)18-6-17-11/h3-6H,1-2H3,(H2,15,17,18)(H2,16,19,20)

Attached Files
20th October 2014 @ 08:34

Summary:

Amination of the product from TF1-1. This is the final step of the synthesis of the thienopyrimidine core component of TF3-1 (Compound 24 in the Series 3 lab book).

Reaction Scheme:

Hazard and Risk Assessment:

RA TF2-1.doc

Procedure:

4-chloro-6-bromo-7-methylthieno[3,2-d]pyrimidine (TF1-1) (100mg, 0.40 mmol), isopropanol (2.25 mL) and ammonia (aq, 28% (w/w), 4.5 mL) were added to a sealed tube, stirred and heated at 120 °C behind a blast shield for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed under vacuum to give a quantitative yield of white solid (108mg, 0.385mmol, 96.25%).

A cross-coupling was then performed on this product in the next stage of the synthesis to form TF3-1.

Data:

TF2-1 1H CDCl3 Raw.tar
TF2-1 1H CDCl3.pdf
TF2-1 13C CDCl3.pdf
TF2-1 Nominal Mass Spec Zoomed.jpg
TF2-1 Nominal Mass Spec.jpg
TF2-1.png
TF2-1 Synthesis.png
TF2-1 High Res MS.jpg

InChi:

InChI=1S/C7H6BrN3S/c1-3-4-5(12-6(3)8)7(9)11-2-10-4/h2H,1H3,(H2,9,10,11)

Attached Files
20th October 2014 @ 08:13

Summary

This is the first step towards the synthesis of TF3-1 (Compound 24 in the Series 3 lab book), as part of an effort to finish off the remaining compounds in Series 3.

Reaction Scheme

 

Hazard and Risk Assessment:

RA 24 Part 1.doc

Procedure

Bromination of the thienopyrimidine core is analogous to the synthesis of AEW99-1.

To 4-chloro-7-methylthieno[3,2-d]pyrimidine (300 mg, 1.758 mmol, 1.0 equiv.) in THF (18 mL) at -78 C was added n-BuLi (1.056 mL, 2.640 mmol, 1.5 equiv.), dropwise with stirring at -78 C for 1 hour. Bromine (0.18 mL, 3.516 mmol, 2.0 equiv.) was added dropwise, and the reaction mixture warmed to RT and stirred for an hour.

The reaction mixture was diluted with an aqueous solution of 1M sodium thiosulfate (5 mL) and extracted into ethyl acetate and water (3 x 25 mL each). The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% ethyl acetate in heptane) to give the desired product as a yield of white crystals (253.9mg, 0.963mmol, 54.8%), and an additional fraction containing an as-of-yet undetermined product as a pale yellow solid (37.3mg).

The product was then aminated in TF2-1.

Data:

TF1-1 Crude Product.pdf
TF1-1 SM.pdf
TF1-1 C1 DCM Raw.tar
TF1-1 C2 Raw.tar
TF1-1 C1 Raw.tar
TF1-1 1H CDCl3.pdf
TF1-1 13C CDCl3.pdf
TF1-1 DEPT135 CDCl3.pdf
TF1-1 DEPT90 CDCl3.pdf
TF1-1 Side Product DCM.pdf
TF1-1 CDCl3 Raw.tar
TF1-1 Nominal Mass Spec.jpg
TF1-1 Nominal Mass Spec Zoomed.jpg
TF1-1 Nominal Mass Spec Side Product.jpg
TF1-1 Synthesis.png
TF1-1.png
TF1-1 High Res MS.jpg

InChi:

InChI=1S/C7H4BrClN2S/c1-3-4-5(12-6(3)8)7(9)11-2-10-4/h2H,1H3

Attached Files
14th October 2014 @ 13:02

Summary:

Cross-coupling of the product from TF2-1 to form TF3-1 (Compound 24 in the Series 3 lab book) The chemistry of this reaction is analogous to PT-22, synthesised by Patrick.

Hazard and Risk Assessment:

RA TF3-1.doc

Reaction Scheme:

 

Procedure:

The combination of the two above building blocks to form compound 24 is analogous to this synthesis alredy performed by Patrick. 

6-bromo-7-methylthieno[3,2-d]pyrimidin-4-amine [TF2] (84.9 mg, 0.3 mmol), MNR103 (141 mg, 0.36 mmol), and Pd(dppf)Cl2 (48 mg, 60 μmol, 20 mol%) were dissolved in isopropyl alcohol (6 mL). Potassium carbonate solution (1M, 0.6 mL) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel.

The product was then purified using column chromatography (0-5% methanol in chloroform for 10 tubes, 5% methanol in chloroform for 20 tubes, 10% methanol in chloroform for 10 tubes) and evaporated to dryness to give a pale brown solid (54.2mg, 0.169mmol, 56.3%). The solid was completely insoluble in chloroform and soluble in methanol.

Data:

TF3-1 Final Product in Methanol-d4.tar
TF3-1 Final Product DEPT90 MeOD.pdf
TF3-1 Final Product 13C MeOD.pdf
TF3-1 Final Product DEPT135 MeOD.pdf
TF3-1 Final Product 1H MeOD.pdf
TF3-1 Nominal Mass Spec (Crude).jpg
TF3-1 Nominal Mass Spec (Crude) Zoomed.jpg
TF3-1 Accurate Mass Spec.jpg
TF3-1.png
TF3-1 Synthesis.png

InChi:

InChI=1S/C13H12N4O2S2/c1-7-10-12(13(14)17-6-16-10)20-11(7)8-3-2-4-9(5-8)21(15,18)19/h2-6H,1H3,(H2,14,16,17)(H2,15,18,19)

Attached Files